Adeno-associated virus (AAV) has been used to program gene expression in a variety of tissues, including heart, liver, skeletal muscle, brain, kidney and lung.1,2 AAV9, in particular, provides highly efficient transduction in cardiac muscle.3,4 However, it has not previously been shown to transduce fibroblasts in vivo, including cardiac fibroblasts.
Studies by Zak5 and Nag6 demonstrated that fibroblasts account for over half of the cardiac cell population in adult rats, although more recent studies have shown that this fraction is lower in mice.? While cardiac fibroblasts are normally quiescent in the heart, after injury they differentiate into myofibroblasts, which are integral to the post-myocardial infarction (MI) wound healing process.8,9 After MI, myofibroblasts infiltrate the infarct zone, where they contribute to scar formation through collagen deposition and the secretion of cytokines, matrix metalloproteinases, and growth factors.7,10 While this normal healing response is crucial to prevent cardiac rupture, it generates non-contractile scar instead of regenerating viable myocardium. As a result, infarct-targeted therapies are needed to reprogram the post-infarct healing process away from scar formation and towards cardiac regeneration.7,11,12 Previous studies have targeted gene therapy to cardiomyocytes,11 but the ability to modulate myofibroblast behavior would open new avenues of therapy to treat LV remodeling in patients recovering from MI.
Several serotypes of AAV have been used to transduce fibroblasts in vitro. Studies using AAV6, -8 and -9 in cultures of human corneal fibroblasts have demonstrated 25-50 fold greater transgene expression using AAV6 as compared to the other two serotypes.13 However, despite this success in cell culture, AAV has not been shown to efficiently transduce fibroblasts, cardiac or otherwise, in vivo. Because a variety of AAV serotypes transduce cardiomyocytes after systemic administration,2,14 any therapy aimed at cardiac fibroblasts would benefit from a promoter that minimizes transcription of exogenous genes in cardiomyocytes to avoid off-target effects. Lindsley et al. dissected a 3.9 kilobase promoter responsible for controlling the transcription of periostin, an epithelial ligand and matricellular protein commonly expressed by fibroblasts.9,15,16 
There is a long felt need in the art for compositions and methods useful for treating myocardial infarction and similar cardiac injuries, diseases, and disorders. The present invention satisfies these needs.